Thrombospondin-1 is a glucocorticoid responsive protein in humans

Abstract

Objective: Thrombospondin-1 (TSP1) is a matricellular protein whose gene expression has previously been shown to increase acutely after exposure to dexamethasone in vitro. The aim of this study was to determine if TSP1 is altered by acute and chronic states of glucocorticoid excess in human subjects. Design and methods: Three studies have been undertaken to assess the difference or change in TSP1 in response to altered glucocorticoid activity: i) an acute interventional study assessed the effects of a single 4 mg dose of dexamethasone in 20 healthy volunteers; ii) a cross-sectional study compared plasma TSP1 in 20 healthy volunteers and eight patients with Cushing's syndrome; iii) an interventional study assessed the effect on plasma TSP1 of an increase in hydrocortisone dose from %20 mg/day to 30 mg/day for 7 days in 16 patients with secondary adrenal insufficiency. Results: In healthy volunteers, 4 mg dexamethasone significantly increased peripheral blood mononuclear cell (PBMC) TSP1 mRNA levels (P!0.0001) and plasma TSP1 concentrations (P!0.0001), peaking at 12 h. Median (interquartile range) plasma TSP1 was higher in Cushing's, 638 (535-756) ng/ml, than in healthy volunteers, 272 (237-336) ng/ml (P!0.0001). Plasma TSP1 O400 ng/ml diagnosed Cushing's syndrome with sensitivity of 100% and specificity of 85%. The higher hydrocortisone dose increased plasma TSP1 from 139 (86-199) to 256 (133-516) ng/ml, (P!0.01) in patients with secondary adrenal insufficiency. Conclusions: TSP1 is a glucocorticoid responsive protein in humans. Further research is required to determine if plasma TSP1 has a role as a glucocorticoid biomarker.

The effect of glucocorticoids on Thrombospondin‐1, Osteocalcin and the Thrombospondin‐1:Osteocalcin ratio in humans

“…11 Platelet activation markedly increases TSP1 levels, 11 Platelet activation markedly increases TSP1 levels,…”

“…Several studies have shown that both TSP1 and OCN are affected by glucocorticoids in humans. 11,13,15 Glucocorticoids inhibit OCN gene expression in osteoblasts via a negative glucocorticoid response element (GRE) in the OCN promoter, 18 but the precise molecular mechanism of the TSP1 induction has not been elucidated.…”

“…The increase in plasma TSP1 after dexamethasone in this group has been previously reported. 11 Figure 3A). Median OCN levels after dexamethasone were 6.8 (5.0-8.8) ng/mL at 0800h and decreased further during the day (P = .0006).…”

“…10 Previously, our group showed that plasma TSP1 increased both in healthy volunteers after a single dose of dexamethasone and in patients with adrenal insufficiency after an increase in their maintenance hydrocortisone and furthermore was elevated in patients with CS, compared with healthy volunteers. 11 Osteocalcin (OCN) is a vitamin K-dependent, noncollagenous protein synthesized by osteoblasts and considered a marker of bone formation. 12 Glucocorticoid-treated patients have decreased OCN levels, reflecting diminished osteoblastic activity.…”

“…Thirdly, the TSP1:OCN ratio increased during the day in patients with AI receiving their daily glucocorticoid supplementation, indicating the effect of replacement therapy.Several studies have shown that both TSP1 and OCN are affected by glucocorticoids in humans 11,13,15. Firstly, the TSP1:OCN ratio increased in HV after a single dose of dexamethasone, and patients on chronic supra-physiological prednisolone treatment had a higher TSP1:OCN ratio compared with HV.…”